Endobiotic biological amines are reactive targets for an assortment of therapeutic and cosmetic moieties. In particular, moieties that contain a carbonyl group, and more particularly an aldehyde or ketone, can interact with said biological amines by forming an imine (Schiff base). Formation of said imine is kinetically slow under physiological conditions and thermodynamically unfavorable.
As one non-limiting example, aliphatic and aryl aldehydes are known to form Schiff base adducts with hemoglobin and impact allosteric oxy-deoxy protein confirmations. Said aldehydes can be used to treat hemoglobinopathies including, but not limited to, sickle cell disease. Sickle cell disease is a global health issue, resulting from an autosomal recessive red blood cell disorder that most commonly affects those of African, Mediterranean and Asian decent (1). Over 13 million people worldwide, including ˜100,000 Americans, are afflicted with the disorder, with ˜300,000 babies born each year with SCD (2). The disease is a caused by an inherited hemoglobinopathy that impairs oxygen binding and enables polymers to form in the red blood cells (RBC), triggering episodes of acute sickle crisis whereby the shapes of the RBC are distorted and become rigid and sickle-shaped (1). The genetic mutation is manifested physiologically as the altered morphologically sickled RBC occlude circulation, resulting in localized ischemia, infarction, hemolytic anemia, organ damage and other debilitating acute and chronic effects (1). While the frequency, severity and duration of vaso-occlusive crises can vary amongst individuals, the episodes are extremely painful, recurrent and lead to a high rate of hospitalization and use of acute medical care facilities, with annual costs to the global healthcare system (3). The pain crisis is the hallmark feature of the disease, interfering profoundly with functioning and has defied all attempts to intervene with drugs that target the sickling process (4). One promising approach to treat acute episodes involves the use of aryl aldehydes that interact stoichiometrically with the N-terminal amino group of α-Val1 of HbS, increasing the oxygen affinity and inhibiting the sickling of homozygous sickle red blood cells by affecting allosteric oxy-deoxy conformational transitions (6). The resultant Schiff base adduct is thought to be stabilized by intramolecular interactions between structural aspects of oxy-Hb at the αα-end of the central cavity (6). Preclinical studies with various aldehydes have shown promise in vitro where the hypoxia-induced formation of sickle cells was largely inhibited by high concentrations of aldehyde (7). In addition, certain aldehydes have been shown to prolong the survival time of mice exposed to severe hypoxia and can exhibit favorable pharmacokinetic properties including oral bioavailability, rapid absorption into the blood stream, and high specificity for HbS (7). The clinical utility of these aldehydes requires high concentrations to compensate for the slow rate of Schiff base adduct (aldehyde/Hemoglobin) formation at hemoglobin and it would be advantageous to increase the rate of reaction, and thereby decrease the concentration of therapeutic needed for efficacy.
As another non-limiting example, aldehyde-containing molecules can be used as adjuvants to other interventions (e.g., vaccination) to combat a variety of pathogens, cancers and chronic infections. Non-limiting examples of said aldehydes include, but are not limited to, synthetic and natural saponin fractions QS-21 from Quillaja saponaria. It has recently been demonstrated unequivocally that the QS-21 isomeric constituents are responsible for the adjuvanticity of the saponin fractions, and that the aldehyde located on the triterpene is required for the adjuvant mechanism of action through Schiff base interaction with a cellular target. The saponin fraction of QS-21 has been demonstrated to be a potent immunological adjuvant when mixed with keyhole limpet hemocyanin conjugate vaccines, as well as with other classes of subunit antigen vaccines. QS-21 adjuvant is composed of two isomers that include the apiose and xylose forms in a ratio of 65:35, respectively. The chemical syntheses of these two isomers in pure form have recently been disclosed).
As another non-limiting example, synthetic immune response modifiers including, but not limited to, Tucaresol (4(2-formyl-3-hydroxy-phenoxymethyl) benzoic acid) and its derivatives, and Isotucaresol and its derivatives can form Schiff base adducts with T-cell surface amines and, in the presence of an antigen, provides co-stimulatory signals to CD4+ T-cells, enhancing Th-cell priming and CD8 cytotoxic T-cell priming; leading to favorable therapeutic activity profiles in vivo (2-7). Results from a Tucaresol Phase I/II pilot study in HIV-positive patients show an increase in CD4+ counts, increase in cytotoxic effector T lymphocytes (CD8+/28−/45RA/57+), increase in HIV-specific CD8+, increase in IFN-□□ and increase in perforin-producing cells, while leaving HIV viraemia unaffected (6). Unfortunately, Tucaresol-related serious adverse events were observed in two patients (2/21) after the first dose and in patients that were viraemic when commencing treatment (6). Unnecessarily large concentrations of Tucaresol must be administered to elicit an efficacious response, as the physiological environment in vivo (pH=7.4) provides an unfavorable setting for rapid Schiff base formation between the Tucaresol aldehyde and T-cell amine to occur. The slow rate of Schiff base formation at T-cell amines and rapid clearance of small molecules by the renal system results in the majority of Tucaresol being unreacted and wasted (2,3). It would be advantageous to accelerate the rate of Schiff base formation in order to mitigate the dose of Tucaresol required for efficacy, and decrease the likelihood of adverse effects.
Carbonyl containing moieties are also useful for cosmetic applications. As another non-limiting example, reducing sugars including, but not limited to, dihydroxyacetone (DHA) and erythrulose are useful to impart a “tanned appearance” on the skin, and widely used in sunless tanning applications. In these applications, the reducing sugar forms a Schiff base adduct with amines of the skin and undergoes subsequent Maillard type reactions to form brown colored compounds that are responsible for the tanned appearance that is associated with sunless tanners. Ketoses containing greater than 5 carbons, and aldoses containing greater than 4 carbons exist predominantly in the cyclic, unreactive form and react kinetically slow with proteins of the skin. As such, their utility in sunless tanning preparations is extremely limited.
The physiological environment in vivo can limit the practical utility of said carbonyl molecules as physiological conditions provide an unfavorable setting for rapid Schiff base formation between a carbonyl (ketone or aldehyde) and endobiotic biological amine to occur. As the kinetics of Schiff base formation at endobiotic amines is slow and small molecules are rapidly cleared by the renal system or washed away from the skin/hair/nails, the majority of said aldehyde or ketone can remain unreacted and wasted. It would be advantageous to accelerate the rate of Schiff base formation with endobiotic amines and herein we provide a method to do so.